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A synaptic and circuit basis for corollary discharge in the auditory cortex

Abstract

Sensory regions of the brain integrate environmental cues with copies of motor-related signals important for imminent and ongoing movements. In mammals, signals propagating from the motor cortex to the auditory cortex are thought to have a critical role in normal hearing and behaviour, yet the synaptic and circuit mechanisms by which these motor-related signals influence auditory cortical activity remain poorly understood. Using in vivo intracellular recordings in behaving mice, we find that excitatory neurons in the auditory cortex are suppressed before and during movement, owing in part to increased activity of local parvalbumin-positive interneurons. Electrophysiology and optogenetic gain- and loss-of-function experiments reveal that motor-related changes in auditory cortical dynamics are driven by a subset of neurons in the secondary motor cortex that innervate the auditory cortex and are active during movement. These findings provide a synaptic and circuit basis for the motor-related corollary discharge hypothesized to facilitate hearing and auditory-guided behaviours.

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Figure 1: Movement modulates membrane potential dynamics of auditory cortical neurons.
Figure 2: Auditory cortical excitatory neurons are suppressed during movement.
Figure 3: Auditory cortical PV+ interneurons and M2ACtx neurons are active during movement.
Figure 4: M2 axon terminals in the auditory cortex are sufficient to produce movement-like auditory cortical dynamics during rest.
Figure 5: M2 activity is necessary to sustain movement-related dynamics in the auditory cortex.

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Acknowledgements

We thank the members of the Mooney laboratory for discussions regarding experimental design and data analysis; S. Lisberger, F. Wang and S. Shea for their valuable comments on the manuscript; and M. Booze for technical support and animal husbandry. D.M.S. is a fellow of the Helen Hay Whitney Foundation; A.N. was supported by the Holland-Trice Graduate Fellowship in Brain Sciences; R.M. was supported by NIH grant NS079929.

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Authors and Affiliations

Authors

Contributions

D.M.S., A.N. and R.M. initiated the project and designed the experiments. D.M.S. performed electrophysiological, optogenetic, and pharmacological experiments in head-fixed mice. A.N. performed electrophysiological experiments in unrestrained mice, two-photon calcium imaging in head-fixed mice, immunohistochemistry, and imaging. D.M.S. and A.N. analysed the data. D.M.S., A.N. and R.M. prepared the manuscript.

Corresponding author

Correspondence to Richard Mooney.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Analysis of behaviour in unrestrained and head-fixed mice.

a, The miniature-motorized microdrive used for making intracellular recordings from unrestrained mice. b, Video still of unrestrained mouse in a circular arena during microdrive recording. Green circle indicates full-field ROI that was used for semi-automated movement detection. c, Changes in pixel intensity over time were measured to detect movements and the heat map shows the average change in pixel intensity across frames for a 2-s clip. Image in c shows a back-and-forth head movement as indicated by green arrows. d, As in c, but for translocation in the direction indicated by the green arrow. e, Video still of head-restrained mouse positioned on a circular treadmill. Green polygons show regions of interest for the treadmill (T), body (B), forelimb (L) and facial (M), with labels shown in f. fi, Heat maps showing average movement for 2-s video clips during running (f), forelimb movements (g), grooming (h) and facial movements (i).

Extended Data Figure 2 Motor-related dynamics across a variety of behaviours.

a, Top shows spectrogram of sound recorded during microdrive experiment, bottom is simultaneous current-clamp recording from auditory cortical excitatory neuron. Left panel shows rest, middle panel shows movement, and right panel shows vocalization (n = 5 cells from 3 mice; moving versus moving and vocalizing, P = 0.3733, paired t-test). b, Normalized membrane potential variance during rest, body movements, and vocalizations. c, Spectrograms of head-fixed mouse on treadmill during 5-s periods of rest (top) and running (bottom). d, Power spectra of sound measured during rest and running. The power spectra are indistinguishable at frequencies greater than 12 kHz. e, Mean root mean square (RMS) power (in dB sound pressure level (SPL)) of tone playback (80 dB), running (43 dB) and rest (42 dB). f, Left panels show static images of head-fixed mouse with heat maps indicating regions of movement during the movement epochs shown at right. Right panels show current-clamp recordings during the movements depicted on the left. g, Change in membrane potential variance (left) and mean (right) for 5 examples of unique movements and 4 examples of vocalization (n = 5 cells from 5 mice for non-vocalizing movements). h, Change in variance as a function of recording depth.

Extended Data Figure 3 Motor-related dynamics persist in broadband masking noise.

a, Example neuron recorded during movement and rest and during periods of silence (left) and 83 dB white noise playback (right). Top panel shows ambient environment, middle panel shows treadmill velocity, and bottom panel shows membrane potential. b, White noise masking abolishes tone-evoked responses (n = 5 cells from 2 mice, P < 0.05, paired t-test). c, Masking does not alter changes in membrane potential variance or mean exhibited during movement (n = 6 cells from 2 mice).

Extended Data Figure 4 Tone-evoked responses are suppressed during movement.

a, Tone-evoked synaptic responses from 20 auditory cortical excitatory neurons during rest (left) and during movement (right). Black dashed lines show tone onset and offset. The tone presented to each neuron was chosen to evoke the largest response (n = 20 cells from 6 mice). b, Mean synaptic responses from a single neuron to multiple presentations of tones presented at multiple frequencies. Black shows response during rest, red shows response during movement. Black bars indicate duration of tone.

Extended Data Figure 5 Excitability and input resistance decrease during movement.

a, Confocal micrograph of ChR2+ thalamocortical terminals (green) amidst neurons immunostained for NeuN (magenta). b, Top panel shows spiking response of an auditory cortical excitatory neuron recorded in treadmill preparation to positive current pulses injected with the recording electrode. Bottom trace shows treadmill movement. The onset of motor-related changes in excitability (black triangle) precedes movement onset (red triangle). c, Top panel shows membrane potential response of an auditory cortical excitatory neuron to negative current pulses injected with the recording pipette. Bottom trace shows treadmill movement. d, Average hyperpolarizing response to negative current pulses injected during rest (black) and during movement (red).

Extended Data Figure 6 Estimating the reversal potential of motor-related currents.

a, Auditory cortical excitatory neuron recorded with treadmill preparation as mouse transitions from rest to movement and back to rest. Top panel shows treadmill movement. Prior to and throughout movement, neuron was depolarized with positive current injection with recording pipette. b, Same neuron as a, but with no current injection. c, Same neuron as a, but with hyperpolarizing current injection. d, Change in mean membrane potential during movement relative to rest as a function of the membrane potential before movement for 4 neurons from 4 mice. Filled circles indicate movements without current injection. Open circles show movements with depolarizing current injection. Open squares show movements with hyperpolarizing current injection. Movement-related modulation of mean membrane potential switches from depolarizing to hyperpolarizing when the resting membrane potential exceeds approximately −72 mV.

Extended Data Figure 7 Inhibitory activity increases during movement.

a, Composite micrograph of a coronal slice of auditory cortex from a VGAT–ChR2–YFP mouse, immunostained for YFP (yellow fluorescent protein; green) and parvalbumin (PV, magenta). b, High magnification image of a section from a, showing both PV+ (magenta) and PV interneurons expressing ChR2 (green). c, Scatter plot showing action potential width and peak-to-valley ratio for all identified PV+ interneurons (green), identified VGAT+ interneurons (magenta), and putative excitatory neurons (grey) in the auditory cortex. d, Identified PV+ interneuron recorded from PV–ChR2 mouse. Top panel shows treadmill velocity (red), instantaneous firing rate (green) and raw voltage trace (black) recorded during laser stimulation (blue shaded regions), rest and locomotion. Instantaneous firing rate during laser stimulation was truncated and reaches a maximum of 500 spikes per s. Red triangle indicates time of movement onset. Bottom left shows overlaid action potential waveforms produced during laser stimulation (black, n = 3) and locomotion (red, n = 3). Bottom right shows average sound-evoked response to tone presented at neuron’s preferred frequency. e. Normalized change in firing rate aligned to movement onset for PV+ neurons (green, described in main figure), VGAT+ interneurons (pink, n = 37 cells from 3 mice) and putative excitatory neurons (grey, described in main figure).

Extended Data Figure 8 M2 activity drives motor-related changes in auditory cortical dynamics.

a, Z-stack micrograph of M2 axons (green, AAV-GFP injection) forming appositions with PV+ immunostained interneurons in auditory cortex (magenta). Inset shows a high magnification single (2 μm) optical section of an apposition. b, M2 spiking activity relative to movement onset (left) and offset (right), normalized to pre-movement activity (n = 90 cells from 3 mice). c, Three simultaneously recorded M2 neurons during three transitions from rest to movement. Top panel shows movement extracted from video (arbitrary units, a.u.). d, Cell bodies and local terminal field of ChR2+ neurons following injection of AAV.2/1.ChR2 into M2. Image is overlaid with an atlas from the Allen Brain Institute. e, Extracellular recordings in M1 of VGAT–ChR2 mouse during blue laser stimulation over ipsilateral M2 showing no change in firing of neurons with broad (black, putative excitatory) or narrow (green, putative inhibitory) neurons (n = 17 cells from 1 mouse). f, Change in membrane potential variance of auditory cortical excitatory neurons over time during optogenetic silencing of either ipsilateral (black, solid, n = 10 cells from 6 mice) or contralateral (grey, dashed, n = 5 cells from 2 mice) M2. For each neuron, the time-varying membrane potential variance was measured during a sliding window that extended 500 ms into the past. Traces were then averaged across neurons after aligning each to the time of movement cessation. Silencing ipsilateral M2 causes membrane potential variance to change before movement offset, whereas silencing contralateral M2 causes the variance to change after movement offset.

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Schneider, D., Nelson, A. & Mooney, R. A synaptic and circuit basis for corollary discharge in the auditory cortex. Nature 513, 189–194 (2014). https://doi.org/10.1038/nature13724

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